The hair follicle is a self-renewing system characterized by epithelial cell loss due to terminal differentiation that is balanced by new cell formation derived from a population of pluripotent stem cells. Keratinocyte stem cells are slow cycling cells located in the bulge region of the hair follicle that undergo transient proliferation during early anagen; cells in early anagen have been shown to be most susceptible to chemical carcinogenesis. The lower follicular epithelial cells undergo extensive apoptosis at the end of anagen, yet a population of stem cells must remain protected from cell death in order for regeneration of the follicular structure to occur. Stenn et al. (1994) showed expression of Bcl-2 in the bulb, basal layer of the outer root sheath, and in the bulge region during anagen. During telogen (resting phase), Bcl-2 expression was found only in the follicular papilla. Polakowska et al. (1994) found Bcl-2 expression in the bulge region of the developing hair follicle and suggested that Bcl-2 may be a stem cell marker. Others have found expression of Bcl-2 in skin malignancies arising from a keratinocyte origin (Nakagawa et al. 1994). The v-Ha-ras transgenic TG.AC mouse behaves as a genetically initiated model for skin tumorigenesis (Leder et al. 1990). Previous work in our lab has shown that transgene expression is a marker for papillomagenesis since constitutive expression cannot be detected in normal skin (Hansen and Tennant, 1994a). Hansen and Tennant (1994b) localized transgene expression in early pre-papilloma leisons (18 days post-TPA treatment) to the bulge (stem cell) region. Most papilloma-bearing mice eventually develop malignancies, which are usually either squamous cell carcinomas or sarcomas of the dermis. There is typically an increase in the level of transgene expression as leisons progress from benign to malignant. We have also been able to detect an apparant increase in Bcl-2 expression in papilloma, squamous cell carcinomas and sarcomas of the dermis over that observed in normal, non-tumor bearing skin. Since we have observed that transgene expression can be localized to the stem cell region of the follicle, and that Bcl-2 is expressed in tumors arising on the TG.AC mouse, we suggest that: 1) the transgene can be used to determine other stem cell markers, and 2) that progeny from crosses between the Bcl-2 knockout mouse and the TG.AC mouse can be used in tumor experiments to determine the effect of down-modulation of Bcl-2 expression on papilloma formation.